Na(V)1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms
Na(V)1.1 is the primary voltage-gated Na(+) channel in several classes of GABAergic interneurons, and its reduced activity leads to reduced excitability and decreased GABAergic tone. Here, we show that Na(V)1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mice car...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2012-02, Vol.109 (6), p.E368-E377 |
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description | Na(V)1.1 is the primary voltage-gated Na(+) channel in several classes of GABAergic interneurons, and its reduced activity leads to reduced excitability and decreased GABAergic tone. Here, we show that Na(V)1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mice carrying a heterozygous loss of function mutation in the Scn1a gene (Scn1a(+/-)), which encodes the pore-forming α-subunit of the Na(V)1.1 channel, have longer circadian period than WT mice and lack light-induced phase shifts. In contrast, Scn1a(+/-) mice have exaggerated light-induced negative-masking behavior and normal electroretinogram, suggesting an intact retina light response. Scn1a(+/-) mice show normal light induction of c-Fos and mPer1 mRNA in ventral SCN but impaired gene expression responses in dorsal SCN. Electrical stimulation of the optic chiasm elicits reduced calcium transients and impaired ventro-dorsal communication in SCN neurons from Scn1a(+/-) mice, and this communication is barely detectable in the homozygous gene KO (Scn1a(-/-)). Enhancement of GABAergic transmission with tiagabine plus clonazepam partially rescues the effects of deletion of Na(V)1.1 on circadian period and phase shifting. Our report demonstrates that a specific voltage-gated Na(+) channel and its associated impairment of SCN interneuronal communication lead to major deficits in the function of the master circadian pacemaker. Heterozygous loss of Na(V)1.1 channels is the underlying cause for severe myoclonic epilepsy of infancy; the circadian deficits that we report may contribute to sleep disorders in severe myoclonic epilepsy of infancy patients. |
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Here, we show that Na(V)1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mice carrying a heterozygous loss of function mutation in the Scn1a gene (Scn1a(+/-)), which encodes the pore-forming α-subunit of the Na(V)1.1 channel, have longer circadian period than WT mice and lack light-induced phase shifts. In contrast, Scn1a(+/-) mice have exaggerated light-induced negative-masking behavior and normal electroretinogram, suggesting an intact retina light response. Scn1a(+/-) mice show normal light induction of c-Fos and mPer1 mRNA in ventral SCN but impaired gene expression responses in dorsal SCN. Electrical stimulation of the optic chiasm elicits reduced calcium transients and impaired ventro-dorsal communication in SCN neurons from Scn1a(+/-) mice, and this communication is barely detectable in the homozygous gene KO (Scn1a(-/-)). Enhancement of GABAergic transmission with tiagabine plus clonazepam partially rescues the effects of deletion of Na(V)1.1 on circadian period and phase shifting. Our report demonstrates that a specific voltage-gated Na(+) channel and its associated impairment of SCN interneuronal communication lead to major deficits in the function of the master circadian pacemaker. Heterozygous loss of Na(V)1.1 channels is the underlying cause for severe myoclonic epilepsy of infancy; the circadian deficits that we report may contribute to sleep disorders in severe myoclonic epilepsy of infancy patients.</description><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1115729109</identifier><identifier>PMID: 22223655</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Behavior, Animal - radiation effects ; Cell Communication - genetics ; Cell Communication - radiation effects ; Circadian Rhythm - genetics ; Circadian Rhythm - physiology ; Circadian Rhythm - radiation effects ; CLOCK Proteins - genetics ; CLOCK Proteins - metabolism ; Electroretinography ; Extracellular Space - metabolism ; Extracellular Space - radiation effects ; Female ; GABAergic Neurons - cytology ; GABAergic Neurons - metabolism ; Gene Expression Regulation - radiation effects ; Light ; Male ; Mice ; Mice, Inbred C57BL ; NAV1.1 Voltage-Gated Sodium Channel ; Nerve Tissue Proteins - metabolism ; Phenotype ; Photic Stimulation ; Signal Transduction - genetics ; Sodium Channels - metabolism ; Suprachiasmatic Nucleus - cytology ; Suprachiasmatic Nucleus - metabolism ; Suprachiasmatic Nucleus - radiation effects ; Synaptic Transmission - genetics ; Synaptic Transmission - radiation effects</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2012-02, Vol.109 (6), p.E368-E377</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22223655$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Han, Sung</creatorcontrib><creatorcontrib>Yu, Frank H</creatorcontrib><creatorcontrib>Schwartz, Michael D</creatorcontrib><creatorcontrib>Linton, Jonathan D</creatorcontrib><creatorcontrib>Bosma, Martha M</creatorcontrib><creatorcontrib>Hurley, James B</creatorcontrib><creatorcontrib>Catterall, William A</creatorcontrib><creatorcontrib>de la Iglesia, Horacio O</creatorcontrib><title>Na(V)1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Na(V)1.1 is the primary voltage-gated Na(+) channel in several classes of GABAergic interneurons, and its reduced activity leads to reduced excitability and decreased GABAergic tone. Here, we show that Na(V)1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mice carrying a heterozygous loss of function mutation in the Scn1a gene (Scn1a(+/-)), which encodes the pore-forming α-subunit of the Na(V)1.1 channel, have longer circadian period than WT mice and lack light-induced phase shifts. In contrast, Scn1a(+/-) mice have exaggerated light-induced negative-masking behavior and normal electroretinogram, suggesting an intact retina light response. Scn1a(+/-) mice show normal light induction of c-Fos and mPer1 mRNA in ventral SCN but impaired gene expression responses in dorsal SCN. Electrical stimulation of the optic chiasm elicits reduced calcium transients and impaired ventro-dorsal communication in SCN neurons from Scn1a(+/-) mice, and this communication is barely detectable in the homozygous gene KO (Scn1a(-/-)). Enhancement of GABAergic transmission with tiagabine plus clonazepam partially rescues the effects of deletion of Na(V)1.1 on circadian period and phase shifting. Our report demonstrates that a specific voltage-gated Na(+) channel and its associated impairment of SCN interneuronal communication lead to major deficits in the function of the master circadian pacemaker. Heterozygous loss of Na(V)1.1 channels is the underlying cause for severe myoclonic epilepsy of infancy; the circadian deficits that we report may contribute to sleep disorders in severe myoclonic epilepsy of infancy patients.</description><subject>Animals</subject><subject>Behavior, Animal - radiation effects</subject><subject>Cell Communication - genetics</subject><subject>Cell Communication - radiation effects</subject><subject>Circadian Rhythm - genetics</subject><subject>Circadian Rhythm - physiology</subject><subject>Circadian Rhythm - radiation effects</subject><subject>CLOCK Proteins - genetics</subject><subject>CLOCK Proteins - metabolism</subject><subject>Electroretinography</subject><subject>Extracellular Space - metabolism</subject><subject>Extracellular Space - radiation effects</subject><subject>Female</subject><subject>GABAergic Neurons - cytology</subject><subject>GABAergic Neurons - metabolism</subject><subject>Gene Expression Regulation - radiation effects</subject><subject>Light</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>NAV1.1 Voltage-Gated Sodium Channel</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Phenotype</subject><subject>Photic Stimulation</subject><subject>Signal Transduction - genetics</subject><subject>Sodium Channels - metabolism</subject><subject>Suprachiasmatic Nucleus - cytology</subject><subject>Suprachiasmatic Nucleus - metabolism</subject><subject>Suprachiasmatic Nucleus - radiation effects</subject><subject>Synaptic Transmission - genetics</subject><subject>Synaptic Transmission - radiation effects</subject><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kL1PwzAQxS0kREthZkPegCHF5zhJMyLEl1TBAqzR5eIoRrET7GTowt-OgXLDPene0096x9gZiDWIIr0eHYY1AGSFLEGUB2wZNyS5KsWCHYfwIYQos404YgsZJ82zbMm-nvHy_QrWwKlD53QfOHrNyZvJEPa8HTw3btKedN_PPXpOg7Wzi-ZkBhc9PnWah3n0SJ3BYOOduJup13NkueYX4QZvI42MJ2wMOu673dTZcMIOW-yDPt3rir3d373ePibbl4en25ttMoISU1LXOitIqlxuUgBKSSuSKGvEsoUCaqVwk6uCRJ2XgHWbo2wQ21TJtqFCFemKXfxxRz98zjpMlTXhpxI6PcyhKiWAyoSCmDzfJ-fa6qYavbHod9X_y9Jvyrduxg</recordid><startdate>20120207</startdate><enddate>20120207</enddate><creator>Han, Sung</creator><creator>Yu, Frank H</creator><creator>Schwartz, Michael D</creator><creator>Linton, Jonathan D</creator><creator>Bosma, Martha M</creator><creator>Hurley, James B</creator><creator>Catterall, William A</creator><creator>de la Iglesia, Horacio O</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20120207</creationdate><title>Na(V)1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms</title><author>Han, Sung ; Yu, Frank H ; Schwartz, Michael D ; Linton, Jonathan D ; Bosma, Martha M ; Hurley, James B ; Catterall, William A ; de la Iglesia, Horacio O</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p140t-bbe57c24628311c3ce4c2a2baa9f171b44a8647c0b691abf6a2daaf342fdc7473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Behavior, Animal - radiation effects</topic><topic>Cell Communication - genetics</topic><topic>Cell Communication - radiation effects</topic><topic>Circadian Rhythm - genetics</topic><topic>Circadian Rhythm - physiology</topic><topic>Circadian Rhythm - radiation effects</topic><topic>CLOCK Proteins - genetics</topic><topic>CLOCK Proteins - metabolism</topic><topic>Electroretinography</topic><topic>Extracellular Space - metabolism</topic><topic>Extracellular Space - radiation effects</topic><topic>Female</topic><topic>GABAergic Neurons - cytology</topic><topic>GABAergic Neurons - metabolism</topic><topic>Gene Expression Regulation - radiation effects</topic><topic>Light</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>NAV1.1 Voltage-Gated Sodium Channel</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Phenotype</topic><topic>Photic Stimulation</topic><topic>Signal Transduction - genetics</topic><topic>Sodium Channels - metabolism</topic><topic>Suprachiasmatic Nucleus - cytology</topic><topic>Suprachiasmatic Nucleus - metabolism</topic><topic>Suprachiasmatic Nucleus - radiation effects</topic><topic>Synaptic Transmission - genetics</topic><topic>Synaptic Transmission - radiation effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Han, Sung</creatorcontrib><creatorcontrib>Yu, Frank H</creatorcontrib><creatorcontrib>Schwartz, Michael D</creatorcontrib><creatorcontrib>Linton, Jonathan D</creatorcontrib><creatorcontrib>Bosma, Martha M</creatorcontrib><creatorcontrib>Hurley, James B</creatorcontrib><creatorcontrib>Catterall, William A</creatorcontrib><creatorcontrib>de la Iglesia, Horacio O</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Han, Sung</au><au>Yu, Frank H</au><au>Schwartz, Michael D</au><au>Linton, Jonathan D</au><au>Bosma, Martha M</au><au>Hurley, James B</au><au>Catterall, William A</au><au>de la Iglesia, Horacio O</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Na(V)1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2012-02-07</date><risdate>2012</risdate><volume>109</volume><issue>6</issue><spage>E368</spage><epage>E377</epage><pages>E368-E377</pages><eissn>1091-6490</eissn><abstract>Na(V)1.1 is the primary voltage-gated Na(+) channel in several classes of GABAergic interneurons, and its reduced activity leads to reduced excitability and decreased GABAergic tone. Here, we show that Na(V)1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mice carrying a heterozygous loss of function mutation in the Scn1a gene (Scn1a(+/-)), which encodes the pore-forming α-subunit of the Na(V)1.1 channel, have longer circadian period than WT mice and lack light-induced phase shifts. In contrast, Scn1a(+/-) mice have exaggerated light-induced negative-masking behavior and normal electroretinogram, suggesting an intact retina light response. Scn1a(+/-) mice show normal light induction of c-Fos and mPer1 mRNA in ventral SCN but impaired gene expression responses in dorsal SCN. Electrical stimulation of the optic chiasm elicits reduced calcium transients and impaired ventro-dorsal communication in SCN neurons from Scn1a(+/-) mice, and this communication is barely detectable in the homozygous gene KO (Scn1a(-/-)). Enhancement of GABAergic transmission with tiagabine plus clonazepam partially rescues the effects of deletion of Na(V)1.1 on circadian period and phase shifting. Our report demonstrates that a specific voltage-gated Na(+) channel and its associated impairment of SCN interneuronal communication lead to major deficits in the function of the master circadian pacemaker. Heterozygous loss of Na(V)1.1 channels is the underlying cause for severe myoclonic epilepsy of infancy; the circadian deficits that we report may contribute to sleep disorders in severe myoclonic epilepsy of infancy patients.</abstract><cop>United States</cop><pmid>22223655</pmid><doi>10.1073/pnas.1115729109</doi><oa>free_for_read</oa></addata></record> |
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subjects | Animals Behavior, Animal - radiation effects Cell Communication - genetics Cell Communication - radiation effects Circadian Rhythm - genetics Circadian Rhythm - physiology Circadian Rhythm - radiation effects CLOCK Proteins - genetics CLOCK Proteins - metabolism Electroretinography Extracellular Space - metabolism Extracellular Space - radiation effects Female GABAergic Neurons - cytology GABAergic Neurons - metabolism Gene Expression Regulation - radiation effects Light Male Mice Mice, Inbred C57BL NAV1.1 Voltage-Gated Sodium Channel Nerve Tissue Proteins - metabolism Phenotype Photic Stimulation Signal Transduction - genetics Sodium Channels - metabolism Suprachiasmatic Nucleus - cytology Suprachiasmatic Nucleus - metabolism Suprachiasmatic Nucleus - radiation effects Synaptic Transmission - genetics Synaptic Transmission - radiation effects |
title | Na(V)1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms |
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